Receptors located in the cell membrane permit communication between cells and thus are arguably the most important molecule in the signal transduction pathway. Receptors with intrinsic tyrosine kinase activity mediate diverse biological responses by binding growth factors and hormones. Ligand binding promotes contact between adjacent receptors leading to receptor oligomerization. This change in the oligomeric structure of the receptor turns these extracellular binding events into an intracellular signal,elevated kinase activity, Alternatively, abnormally high expression of receptors promotes spontaneous oligomerization that triggers the protein kinase cascade. Indeed, the most common cellular lesion found in human cancers involves receptor overexpression. In approximately 30% of human breast cancers, a growth factor receptor (ErbB2) is overproduced, resulting in spontaneous receptor dimerization and aggressive uncontrolled growth of breast tumor cells. Drugs are needed to block dimer formation by the EGF family of receptors (ErbB1-4), since this family has been implicated more than any other in the development of human carcinomas. To accomplish this goal it is essential to determine the quaternary structural requirements for receptor dimer formation by the extracellular domain. The specific aims of this application are to: 1) determine the atomic structure of the extracellular domain of ErbB2 by X-ray crystallography; 2) screen a small molecule data base for potential drugs that bind to this interface; and 3) evaluate potential compounds in an in vitro proliferation assay.